The present invention relates to microfluidic synthesis devices and methods for their use and manufacture. These devices and methods are useful in performing microfluidic-scale chemical and biological synthesis reactions, including chemical and biological syntheses of organic, polymer, inorganic, oligonucleotide, peptide, protein, bacteria, and enzymatic products.
There has been a growing interest in the manufacture and use of microfluidic systems for the acquisition of chemical and biological information. In particular, when conducted in microfluidic volumes, complicated biochemical reactions may be carried out using very small volumes of liquid. Among other benefits, microfluidic systems increase the response time of reactions, minimize sample volume, and lower reagent consumption. When volatile or hazardous materials are used or generated, performing reactions in microfluidic volumes also enhances safety and reduces disposal quantities.
Traditionally, microfluidic devices have been constructed in a planar fashion using techniques that are borrowed from the silicon fabrication industry. Representative systems are described, for example, in some early work by Manz et al. (Trends in Anal. Chem. 10(5): 144-149; Advances in Chromatography (1993) 33: 1-66). In these publications, microfluidic devices are constructed by using photolithography to define channels on silicon or glass substrates and etching techniques to remove material from the substrate to form the channels. A cover plate is bonded to the top of the device to provide closure. Miniature pumps and valves can also be constructed to be integral (e.g., within) such devices. Alternatively, separate or off-line pumping mechanisms are contemplated.
More recently, a number of methods have been developed that allow microfluidic devices to be constructed from plastic, silicone or other polymeric materials. In one such method, a negative mold is first constructed, and plastic or silicone is then poured into or over the mold. The mold can be constructed using a silicon wafer (see, e.g., Duffy et al., Analytical Chemistry (1998) 70: 4974-4984; McCormick et. al., Analytical Chemistry (1997) 69: 2626 2630), or by building a traditional injection molding cavity for plastic devices. Some molding facilities have developed techniques to construct extremely small molds. Components constructed using a LIGA technique have been developed at the Karolsruhe Nuclear Research center in Germany (see, e.g., Schomburg et al., Journal of Micromechanical Microengineering (1994) 4:186-191), and commercialized by MicroParts (Dortmund, Germany). Jenoptik (Jena, Germany) also uses LIGA and a hot-embossing technique. Imprinting methods in PMMA have also been demonstrated (see, Martynova et. al., Analytical Chemistry (1997) 69: 4783-4789) However, these techniques do not lend themselves to rapid prototyping and manufacturing flexibility. Additionally, the foregoing references teach only the preparation of planar microfluidic structures. Moreover, the tool-up costs for both of these techniques are quite high and can be cost-prohibitive.
Synthesis is extremely variable compared to other fields. It would be difficult to fabricate a single microfluidic device capable of performing all of the various functions and handling all of the various chemistries that would be required to perform synthesis generally. For example, various steps of a synthetic process often require different material compatibilities. Additionally, since synthesis requires many reaction steps and the order of those reaction steps varies, fabricating enough devices to enable a broad range of synthetic protocols is impractical using conventional techniques.
Various conventional tools and combinations of tools are used when synthesizing chemical or biological products in conventional macroscopic volumes. Such tools include, for example: metering devices, reactors, valves, heaters, coolers, mixers, splitters, diverters, cannulas, filters, condensers, incubators, separation devices, and catalyst devices. Attempts to perform chemical or biological synthesis in microfluidic volumes have been stifled by difficulties in making tools for synthesis at microfluidic scale and then integrating such tools into microfluidic devices. Another difficulty is accurately measuring stoichiometric microfluidic volumes of reagents and solvents to perform synthesis on a microfluidic scale. Additionally, difficulties in rapidly prototypic microfluidic devices are compounded by attempts to incorporate multiple synthesis tools for multi-step synthesis.
Thus, it would be desirable to provide systems and methods for performing chemical or biological synthesis using microfluidic devices. It also would be desirable to provide modular microfluidic systems that are readily configurable to perform different fluidic operations.
In a first aspect of the present invention, a method for synthesizing products comprises the steps of selecting a desired fluidic operation, selecting a desired product, providing a plurality of microfluidic devices, fluidically coupling least two of the microfluidic devices, and performing a biological or chemical synthesis operation. The microfluidic devices are fabricated with a polymeric material.
In another aspect of the invention, a method for synthesizing products comprises the steps of identifying the desired sequence of operations, providing a plurality of microfluidic modules, fluidically coupling the modules to create an arrangement of modules that enables the sequence of operations to be performed, and providing a fluid to one of the modules. Each module is adapted to perform at least one operation of the sequence of operations. Each module is fabricated with a polymeric material;
In another aspect of the invention, a modular microfluidic system for performing a sequence of operations on a fluid comprises a plurality of modules. Each module is capable of performing at least one operation of the sequence. Each module is fabricated with a polymeric material and a stencil layer. The stencil layer has a characteristic thickness. The module defines a microfluidic structure through the entire thickness of the stencil layer. A microfluidic coupling device, also fabricated with a stencil layer and having a characteristic thickness, defines a microfluidic structure through its entire thickness. The plurality of modules are fluidically coupled to perform the sequence of operations.
In another separate aspect of the invention, any of the foregoing separate aspects may be combined for additional advantage. These and other aspects and advantages of the invention will be apparent to the skilled artisan upon review of the following description, drawings and claims.